PVSRIPO for Patients With Unresectable Melanoma

The Primary Objective of the study is to determine the safety profile of PVSRIPO in Stage
IIIB, IIIC, and IV recurrent melanoma patients as determined by DLTs when PVSRIPO is injected
intralesionally into 1 to 3 cutaneous or subcutaneous lesions. As planned, a minimum of 3
patients will be treated with PVSRIPO, up to a maximum of 9.

A modified 3+3 phase 1 trial design will be implemented over three dosing cohorts (cohorts
0-2), where patients will receive 1 (cohort 0), 2 (cohort 1) or 3 (cohort 2) injections into
individual lesions; if more than 1 lesion is injected, injections will occur 21 days apart.
In cohort 0, a minimum of 3 patients will have one lesion injected with PVSRIPO at 1x10^8
TCID50. If 0 or 1 of 3 have a dose limiting toxicity (DLT; any Grade 4 or higher
non-hematologic toxicities probably, possibly, or definitely related to PVSRIPO; with the
exception of vitiligo; any Grade 4 or higher hematologic toxicities probably, possibly, or
definitely related to PVSRIPO)). within 21 days after injection, three patients will be
enrolled to cohort 1, to receive PVSRIPO at a dose of 1x10^8 TCID50 on day 0 into one index
lesion and a second injection at the same dose (1x10^8 TCID50 ) into a separate lesion on day
21 (±2 days). If 2 or more patients have a DLT in cohort 0, the dose will decrease to 5x10^7
TCID50 and 3 patients will have 1 lesion injected on day 0 and this reduced dose will be
cohort 1. Additional cohorts will be based on the number of toxicities noted. A second
injection of a second lesion may not be given in an individual patient if that patient
experiences a DLT following their first injection.

If 2 of 3 patients in cohort 1 have a DLT, accrual will be temporarily suspended, for a more
detailed review DLTs, before processing to enroll additional patients. If the trial resumes,
it will proceed to a lower second dose per in Cohort 2, or possibly stop the trial. If 2 of
the first 3 patients in cohort 2 have a DLT, safety will be re-assessed before treating a
third patient at that dose level.

Biopsy material will be obtained from tumor tissue prior to first virus administration. This
tissue material may be subjected to routine histology to confirm tumor recurrence by the
study pathologist along with molecular genetic testing if there is sufficient tissue
remaining. Patients may undergo biopsies of injected lesions up to 28 days prior to injection
but no less than 7 days before injection, day 10, and day 84 following each injection, if the
lesion is of sufficient size to obtain biopsy. Surgical excisions will also include
examination of pathologic response. Non injected lesions may also be biopsied pre-treatment,
day 10, and day 84, if tumor burden is sufficient. Whole blood for immunologic analyses will
also be collected throughout the study period.

Routine study visits will occur through Day 126 (including required post injection visits:
Day 84 (1st injection), Day 105 (2nd injection), or Day 126 (3rd injection), as applicable).
Thereafter, visits will occur every 2-3 months following the required for up to 2 years for
subjects who do not progress. For patients with progressive disease, chart review only will
occur every 3 months starting at the time of progression.

Inclusion Criteria:

1. Positive serum anti-poliovirus titer prior to biopsy.

2. The patient must have received a boost immunization with trivalent inactivated IPOL™
(Sanofi-Pasteur) at least 1 week prior to administration of the study agent.

3. Patient must have histologically proven unresectable, recurrent, melanoma, stage IIIB,
IIIC, or stage IV (AJCC staging must be documented in patient's medical record, as
determined by CT of the chest, abdomen and pelvis, and/or whole body PET scan, and MRI
of the brain within 4 weeks prior to administration of study drug).

4. Patients with BRAF mutations, must have failed at least 2 lines of therapy,
specifically one BRAF targeted therapy and at least one anti-PD-1 based therapy. For
BRAF wild type, patients must have failed at least one anti-PD-1 based therapy.

5. Patient must be ≥ 18 years of age.

6. Patient must have an ECOG/Zubrod status of 0-1.

7. Patient's disease must be bi-dimensionally measurable by caliper or radiological
method as defined in the irRC criteria.

8. At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesions ≥ 10 mm in
longest diameter or, multiple injectable melanoma lesions which in aggregate have a
longest diameter of ≥ 10 mm (Cohorts 0 and possibly 1). For cohorts where 2 or 3
injections are planned (Cohorts 1 and 2), the patient must have at least 2 injectable
melanoma lesions (when 2 doses are planned) or 3 injectable melanoma lesions when 3
doses are planned.

9. At least one measurable lesion that will not be injected.

10. Serum lactate dehydrogenase (LDH) levels less than 1.5 x upper limit of normal (ULN).

11. Patient must have adequate bone marrow, liver and renal function as assessed by the
following:

1. Hemoglobin > 9.0 g/dl

2. White blood count (WBC) of > 2000 m3

3. Absolute neutrophil count (ANC) > 1,000/mm3

4. Platelet count > 75,000/mm3

5. Total bilirubin < 2.0 x ULN

6. ALT and AST < 2.5 x the ULN

Exclusion Criteria:

1. Females who are pregnant or breast-feeding.

2. Adults of reproductive potential not employing an effective method of birth control.

3. Patients with severe, active co-morbidity, defined as follows:

1. Patients with an active infection requiring treatment or having an unexplained
febrile illness (Tmax > 99.5°F/37.5°C).

2. Patients with impaired cardiac function or clinically significant cardiac
disease, such as congestive heart failure requiring treatment (New York Heart
Association Class ≥ 2), uncontrolled hypertension or clinically significant
arrhythmia; QTcF > 470 msec on ECG if performed or congenital long QT syndrome;
acute myocardial infarction or unstable angina pectoris < 3 months prior to
study.

3. Patients with known lung (FEV1 < 50%) disease or uncontrolled diabetes mellitus
(HgbA1c>7).

4. Patients with albumin allergy.

5. Autoimmune disease: History of or current active autoimmune diseases, [e.g.
including but not limited to inflammatory bowel diseases [IBD], rheumatoid
arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis
(scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis,
autoimmune neuropathies (such as Guillain-Barre syndrome)]. Vitiligo and
adequately controlled endocrine deficiencies such as hypothyroidism are not
exclusionary.

6. Known immunosuppressive disease, human immunodeficiency virus (HIV) infection, or
chronic Hepatitis B or C.

4. Patients with a previous history of neurological complications due to PV infection.

5. Patients who have not recovered from the toxic effects of prior chemo- and/or
radiation therapy. Guidelines for this recovery period are dependent upon the specific
therapeutic agent being used. Toxicities must have resolved to CTCAE grade 1 or less
with the following exceptions (alopecia, fatigue, vitiligo).

6. Patients with undetectable anti-tetanus toxoid IgG.

7. Patients with known history of agammaglobulinemia.

8. Patients on greater than 10 mg per day of prednisone within the 2 weeks prior to
admission for PVSRIPO injection.

9. Patients with worsening steroid myopathy (history of gradual progression of bilateral
proximal muscle weakness, and atrophy of proximal muscle groups).

10. Patients with prior, unrelated malignancy requiring current active treatment with the
exception of cervical carcinoma in situ and adequately treated basal cell or squamous
cell carcinoma of the skin.

11. Clinically active cerebral or bone metastases.

12. Greater than 3 visceral metastases (this does not include nodal metastases associated
with visceral organs).

13. Prior allogeneic stem cell transplantation.

14. Concomitant therapy with any of the following: IL-2, interferon, or other non-study
immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
investigation therapies; or chronic use of systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses). However, during the course of
the study, use of corticosteroids is allowed if used for treating irAEs, adrenal
insufficiencies, or if administered at doses of prednisone 10 mg daily or equivalent.

15. Active clinically serious infection > CTCAE Grade 2.

16. Antineoplastic therapy, radiotherapy, or any other investigational drug within 15 days
prior to first study drug administration.